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Influenza virus infection causes considerable morbidity and mortality, but current therapies have limited efficacy. We hypothesized that investigating the metabolic signaling during infection may help to design innovative antiviral approaches. Using bronchoalveolar lavages of infected mice, we here demonstrate that influenza virus induces a major reprogramming of lung metabolism. We focused on mitochondria‐derived succinate that accumulated both in the respiratory fluids of virus‐challenged mice and of patients with influenza pneumonia. Notably, succinate displays a potent antiviral activity in vitro as it inhibits the multiplication of influenza A/H1N1 and A/H3N2 strains and strongly decreases virus‐triggered metabolic perturbations and inflammatory responses. Moreover, mice receiving succinate intranasally showed reduced viral loads in lungs and increased survival compared to control animals. The antiviral mechanism involves a succinate‐dependent posttranslational modification, that is, succinylation, of the viral nucleoprotein at the highly conserved K87 residue. Succinylation of viral nucleoprotein altered its electrostatic interactions with viral RNA and further impaired the trafficking of viral ribonucleoprotein complexes. The finding that succinate efficiently disrupts the influenza replication cycle opens up new avenues for improved treatment of influenza pneumonia. Synopsis: Metabolic defense mechanisms of lung epithelial cells exposed to influenza virus infection remain poorly understood. Here, combined metabolomics, in vitro and in vivo infection assays reveal a surprising anti‐viral role of energy production metabolite succinate in the airways, suggesting new avenues for improved treatment of influenza pneumonia. Influenza A virus (IAV) infection of mice increases succinate levels in the airways.IAV‐infected patients show elevated succinate levels in tracheal aspirates.Succinate inhibits IAV infection through succinylation and nuclear retention of the viral nucleoprotein.Succinate restores metabolic dysregulation in IAV‐infected lung epithelial cells and impairs acute influenza pneumonia in vivo. [ABSTRACT FROM AUTHOR]

Autoimmunity, IgE, immunotherapy clinical, interleukins, T cells Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Keywords: autoimmunity; IgE; immunotherapy clinical; interleukins; T cells EN autoimmunity IgE immunotherapy clinical interleukins T cells 2924 2926 3 09/03/21 20210901 NES 210901 Jan Egbert de Vries (Figure 1) is a cosmopolitan immunologist and an enthralling mentor with a large track record of innovative achievements in the fields of allergy and immunology. [Extracted from the article]

Abstract: Mucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is essential for immune responses triggered by antigen receptors but the contribution of its paracaspase activity is not fully understood. Here, we studied how MALT1 proteolytic function regulates T‐cell activation and fate after engagement of the T‐cell receptor pathway. We show that MLT‐827, a potent and selective MALT1 paracaspase inhibitor, does not prevent the initial phase of T‐cell activation, in contrast to the pan‐protein kinase C inhibitor AEB071. However, MLT‐827 strongly impacted cell expansion after activation. We demonstrate this is the consequence of profound inhibition of IL‐2 production as well as reduced expression of the IL‐2 receptor alpha subunit (CD25), resulting from defective canonical NF‐κB activation and accelerated mRNA turnover mechanisms. Accordingly, MLT‐827 revealed a unique transcriptional fingerprint of MALT1 protease activity, providing evidence for broad control of T‐cell signaling pathways. Altogether, this first report with a potent and selective inhibitor elucidates how MALT1 paracaspase activity integrates several T‐cell activation pathways and indirectly controls gamma‐chain receptor dependent survival, to impact on T‐cell expansion. [ABSTRACT FROM AUTHOR]

Dieckhoff K, Graf P, Beinhauer B, Schwaerzler C, Carballido JM, Neumann C, Zachmann K, Jung T. Deficient translocation of c-Rel is associated with impaired Th1 cytokine production in T cells from atopic dermatitis patients.Decreased production of T helper type 1 (Th1) cytokines, such as interferon-γ (IFN-γ) or interleukin-2 (IL-2), is a hallmark of atopic diseases. While accessory signals from antigen-presenting cells may be missing, T cells themselves may be suppressed in their ability to produce substantial amounts of Th1 cytokines. We show, in this study, that T cell receptor (TCR)-activated T cells from atopic dermatitis (AD) patients proliferate less than control T cells and produce lower amounts of IFN-γ and IL-2, but comparable amounts of IL-4. Because mice lacking the nuclear factor kappa B (NF-κB) transcription factors– p65 or c-Rel– show reduced Th1, but undisturbed Th2 responses, we investigated the role of c-Rel and p65 for Th1 cytokine production in T cells from healthy and severe AD patients. TCR-activated primary T cells from healthy donors treated with c-Rel antisense oligonucleotides produced lower levels of IL-2 and IFN-γ and proliferated less efficiently than the corresponding control T cells. Moreover, transfection of primary T cells with c-Rel or p65 enhanced proliferation and production of IL-2 and IFN-γ. Nuclear extracts of activated primary T cells from AD donors bound weakly to NF-κB-specific oligonucleotides, compared to extracts from healthy control T cells. Western blotting studies revealed that nuclear, but not cytosolic, extracts from T cells of AD patients lacked significant amounts of c-Rel and p65. T cell clones derived from AD patients failed to sufficiently translocate c-Rel and p65 into the nucleus following activation. Thus, impaired nuclear translocation of c-Rel and p65 may determine an impaired Th1 cytokine response in AD. [ABSTRACT FROM AUTHOR]

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